We have recently defined the surface phenotype of a subset of CD8+ T cells programmed to inhibit the activation and expansion of follicular helper T cells (TFH). These regulatory CD8+ T cells express CD44, CD122 and the inhibitory Ly49 receptor on their surface and a T cell receptor (TCR) that recognizes Qa- 1: peptide complexes expressed by TFH cells. These CD8+ Treg cells, which represent less than 5% of the CD8+ T cell pool, inhibit TFH activity through an IL-15- and perforin-dependent mechanism. The development of collagen-induced arthritis (CIA) is associated with B- and T-lymphocyte responses, production of anti-collagen type II antibodies and collagen-specific T cells. Our preliminary studies of a mouse model of CIA support the hypothesis that enhanced interactions between CD8+ Treg cells and target TFH cells profoundly inhibits disease progression. In this proposal, we further define the interaction between CD8+ Treg and target TFH cells in CIA and a murine model of systemic autoimmunity - B6.-Yaa disease - in an effort to develop strategies that increase the activity of CD8+ Treg and inhibit and/or ameliorate disease development. The experimental approaches outlined below should provide new insights into the role of CD8+ Treg in the regulation of autoimmune diseases and form the basis for new therapeutic approaches to rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and related diseases.